Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14–17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology. We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays. Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency—4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability. We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients—with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.

中文翻译：

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转移性和复发性肾上腺皮质癌的基因组状况尚不确定

肾上腺皮质癌（ACC）是一种罕见的，经常攻击性的肾上腺皮质肿瘤，中位总生存期为14-17个月。我们询问来自患有晚期或转移性ACC的患者的肿瘤是否会提供可能在疾病进展或更具侵略性的疾病生物学中发挥关键作用的推定基因的线索。我们对43例患者，30例女性和42例转移部位的ACC进行了全面的基因组和表达分析，包括深度测序，拷贝数分析，mRNA表达和microRNA阵列。拷贝数的得失与先前报告的ACC相似。我们确定了每兆碱基（Mb）的中位突变率为3.38。突变特征的特征在于主要是C> T，C> A和T> C过渡。只有癌症基因TP53（26％）和β-catenin（CTNNB1，超过10％的样本发生了14％的突变。TCGA鉴定的推定癌症基因MEN1和PRKAR1A的频率较低，分别为4.7％和2.3％。大多数突变是与癌症的病因或维持无关的基因。具体而言，在超过9％的样本中发生突变的38个基因中，只有576个COSMIC癌症基因普查（CCGC）的方法1中代表了四个基因。因此，发现有突变的基因中有82％可能与ACC的病因或生物学无关。而其他18％（如果有）的作用还有待证明。最后，ACC中38个最频繁突变的基因的转录长度在统计学上比所有编码基因的平均值更长，这提出了转录长度是否部分决定突变概率的问题。我们得出的结论是，晚期和转移性肿瘤的突变和表达谱与新诊断的患者非常相似，几乎没有基因组畸变的方式来解释生物学差异。由于相对较低的突变率，主要的致癌驱动因素很少，以及几个表观遗传调控因子的功能缺失，可以推测ACC的表观遗传基础，并作为未来研究的基础。